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The goal of this study was to evaluate clinical and economic outcomes associated with the initiation of intravenous (IV) belimumab for the treatment of systemic lupus erythematosus (SLE) in clinical practice in the United States.
MethodsThis retrospective study used administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental and Coordination of Benefits Database. Data for patients with SLE who initiated (index) IV belimumab were collected for the 12 months before (pre-index) and the 12 months after (post-index) belimumab initiation. Outcomes included SLE disease severity and flares, all-cause health care resource utilization (HCRU) and health care costs, and hospital-based costs and service visits. Post hoc analyses of total hospital-based costs were conducted to further explore drivers of mean post-index costs.
FindingsBaseline characteristics (N = 908) are as follows: female, 93.4%; mean (SD) age, 45.6 (11.9) years; mean Charlson Comorbidity Index score, 0.9 (2.0); and moderate or severe disease, 94.9%. Disease activity (SLE flare episodes) was significantly reduced between the pre-index and post-index periods (severe flares, 16.4% vs 10.1% [P < 0.0001]; moderate flares, 92.1% vs 85.6% [P < 0.0001]; and mild flares, 77.4% vs 71.1%; [P = 0.0003]). The proportion of patients receiving oral corticosteroids (OCS) was reduced between the pre-index and post-index periods, especially among patients at higher OCS thresholds (prednisone-equivalent dose: ≥60 mg/d, 7.3% vs 4.2%; >40 mg/d, 14.1% vs 7.9%). From the pre-index to the post-index period, few differences in HCRU were observed, although all-cause physician office visits, outpatient visits, and unique prescriptions filled increased significantly. In the 12-month post-index period, patients had a mean of 12.2 (9.0) encounters (eg, outpatient visit or prescription) associated with IV belimumab. All-cause total, medical, and pharmacy costs increased from the pre-index to the post-index period. Mean all-cause hospital-based costs increased from the pre-index to the post-index period ($7735 [26,603] vs $11,030 [88,086]; P = 0.396). However, the 75th, 90th, and 95th percentile costs decreased from the pre-index to the post-index period ($305, $2107, and $3861, respectively).
ImplicationsAfter initiation of IV belimumab, disease activity (number of moderate and severe SLE flares) and use of OCS were significantly reduced. However, HCRU and costs, including hospital-based costs, were generally greater in the post-index period. Further studies will increase understanding of SLE, with the specific goals of incorporating disease activity measures and long-term outcomes in studies of HCRU, costs, and patient outcomes.
IntroductionSystemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with an estimated prevalence in the United States of between 72.1 and 90.4 cases per 100,000 people.1Dall'Era M.C. Snipes K. Cisternas M. Gordon C. Helmick C.G. Preliminary population-based incidence and prevalence estimates of systemic lupus erythematosus: the California Lupus Surveillance Project.,2Somers E.C. Marder W. Cagnoli P. et al.Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. In addition to fatigue and weight loss, patients frequently experience inflammatory skin rash and inflammation of the joints and serous membranes, with renal and central nervous system involvement also seen in severe disease.3Systemic lupus erythematosus: from genes to organ damage. Patients with SLE experience increased periods of disease activity, termed flares, that range in severity and which are associated with increased use of health care services and costs.4Kan H.J. Song X. Johnson B.H. Bechtel B. O'Sullivan D. Molta C.T. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid.,5Garris C. Jhingran P. Bass D. Engel-Nitz N.M. Riedel A. Dennis G. Healthcare utilization and cost of systemic lupus erythematosus in a US managed care health plan. The combination of disease activity, flares, and corticosteroids contributes to the accrual of organ-specific damage, which steadily increases over time.6Conti F. Ceccarelli F. Perricone C. et al.The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort.,7Ugarte-Gil M.F. Acevedo-Vasquez E. Alarcon G.S. et al.The number of flares patients experience impacts on damage accrual in systemic lupus erythematosus: data from a multiethnic Latin American cohort. As such, this patient population requires frequent use of health care resources, including hospitalization, the mean rates of which have been reported to be considerably higher than that of individuals without SLE.4Kan H.J. Song X. Johnson B.H. Bechtel B. O'Sullivan D. Molta C.T. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid.,8Furst D.E. Clarke A. Fernandes A.W. et al.Resource utilization and direct medical costs in adult systemic lupus erythematosus patients from a commercially insured population. Consequently, SLE is associated with substantial disease-related costs, which have been estimated to range from $2214 to $29,232/year per patient.4Kan H.J. Song X. Johnson B.H. Bechtel B. O'Sullivan D. Molta C.T. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid.,8Furst D.E. Clarke A. Fernandes A.W. et al.Resource utilization and direct medical costs in adult systemic lupus erythematosus patients from a commercially insured population., 9Cervera R. Rua-Figueroa I. Gil-Aguado A. et al.Direct cost of management and treatment of active systemic lupus erythematosus and its flares in Spain: the LUCIE Study., 10Doria A. Iaccarino L. La Montagna G. et al.Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy., 11Meacock R. Dale N. Harrison M.J. The humanistic and economic burden of systemic lupus erythematosus: a systematic review. Health care use and costs are particularly high in patients with severe disease and in those who experience severe flares.4Kan H.J. Song X. Johnson B.H. Bechtel B. O'Sullivan D. Molta C.T. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid.,9Cervera R. Rua-Figueroa I. Gil-Aguado A. et al.Direct cost of management and treatment of active systemic lupus erythematosus and its flares in Spain: the LUCIE Study., 10Doria A. Iaccarino L. La Montagna G. et al.Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy., 11Meacock R. Dale N. Harrison M.J. The humanistic and economic burden of systemic lupus erythematosus: a systematic review.Treatment goals in SLE include the management of symptoms, reduction of disease activity (including flares), and prevention of organ damage accrual.12Fanouriakis A. Kostopoulou M. Alunno A. et al.2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus. To achieve these goals, treatment guidelines recommend the use of therapies, including a combination of corticosteroids, antimalarial agents, immunosuppressant drugs, and biologics.12 Belimumab, a recombinant, human monoclonal antibody, selectively inhibits B-cell activating factor (BAFF),13FDAThis retrospective study (GSK Study 209422//HO-18-19386) used administrative claims data collected from January 1, 2012, to March 31, 2017, from the IBM MarketScan Commercial Claims and Encounters Database (commercial) and the Medicare Supplemental and Coordination of Benefits Database (Medicare). The commercial database consists of employer- and health plan–sourced, linked medical and prescription claims data for >50 million individuals. Enrollees include employees, their spouses, and dependents who are covered by employer-sponsored private health insurance. The Medicare supplemental data contain inpatient and linked medical and prescription claims for ~4.3 million Medicare-eligible persons with supplemental insurance plans offered by their former employers.
Primary data were not collected in this study; all data were ascertained from the previously anonymized MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases. Therefore, institutional review board approval and informed consent were not necessary.
Study Design and Sample SelectionThe first IV belimumab administration date during the identification period (January 1, 2012, and March 31, 2016) was defined as the index date, and data for each patient were retrospectively collated for the 12 months before index (pre-index period) and the 12 months after index (post-index period). Patients were required to be ≥18 years of age on the index date, have a diagnosis of SLE (9th revision of the International Classification of Diseases, Clinical Modification [ICD-9-CM], code 710.0 or 10th revision [ICD-10-CM] code M32) at any time during the study period (Figure 1), and evidence of ≥1 belimumab 10 mg/kg IV administration during the identification period (National Drug Classification code 49401010101 or 49401010201; Healthcare Common Procedure Coding System codes Q2044 or J0490). In addition, patients were required to be naive to belimumab treatment during the pre-index period, have no evidence of lupus nephritis according to the 2010 criteria of Chibnik et al22Chibnik L.B. Massarotti E.M. Costenbader K.H. Identification and validation of lupus nephritis cases using administrative data. at any time during the pre-index or post-index periods, and be continuously enrolled in the database with medical and prescription drug coverage for ≥12 months before and after the index date. All patients meeting these criteria were included in the final analysis (intention-to-treat [ITT] population). Patients with ≥4 IV belimumab infusions in the first 6 months post-index were included in the modified ITT (mITT) population.Figure 1Study design. IV = intravenous; SLE = systemic lupus erythematosus.
Study Outcomes/VariablesStudy outcomes/variables included patient baseline characteristics, SLE disease severity and flares, HCRU, all-cause health care costs, costs of belimumab treatment, and treatment patterns.
Baseline characteristics assessed at the index date included age, sex, health plan type, geographic region, index year, and metropolitan statistical area. Clinical variables assessed included SLE-adjusted Charlson Comorbidity Index (CCI) scores23Development and testing of a systemic lupus-specific risk adjustment index for in-hospital mortality. and comorbid conditions, assessed during the pre-index period only. Comorbidities were identified by the presence of ≥1 medical claim using ICD-9/10-CM diagnosis codes. SLE disease severity and number and duration of SLE flare episodes were assessed during the pre-index and post-index periods. SLE disease severity was assessed based on disease activity, cumulative damage and medication use, and flare severity based on medication use and HCRU, as per the criteria in Table I.4Kan H.J. Song X. Johnson B.H. Bechtel B. O'Sullivan D. Molta C.T. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid.,5Garris C. Jhingran P. Bass D. Engel-Nitz N.M. Riedel A. Dennis G. Healthcare utilization and cost of systemic lupus erythematosus in a US managed care health plan.,24Narayanan S. Wilson K. Ogelsby A. Juneau P. Durden E. Economic burden of systemic lupus erythematosus flares and comorbidities in a commercially insured population in the United States. SLE flare duration was set at a minimum duration of 30 days. If a higher severity flare was experienced during an episode, the flare duration was limited to the period between the start of the initial flare and start of the higher severity flare. For flares requiring hospitalization, the start date was the date of inpatient admission or day of emergency department (ED) visit if this was on the previous day. Although not part of the scope of the study, oral corticosteroid (OCS) use (milligram per day prednisone-equivalent dose) was also evaluated by using the thresholds specified in the SLE Disease Severity algorithm.5Garris C. Jhingran P. Bass D. Engel-Nitz N.M. Riedel A. Dennis G. Healthcare utilization and cost of systemic lupus erythematosus in a US managed care health plan. (shown in Table I)Table ICriteria used for determining disease activity and flares.
ED = emergency department; NSAIDS = non-steroidal anti-inflammatory drugs; OCS = oral corticosteroid; SLE = systemic lupus erythematosus.
HCRU outcomes encompassed inpatient admissions, ED visits, physician office visits, outpatient/other ancillary visits, and medication use and were assessed during the pre-index and post-index periods. Treatment pattern outcomes assessed included adherence and discontinuation over the post-index period. Adherence was calculated as the number of days covered by an IV infusion (based on the belimumab prescribing information), divided by the actual number of days that accrued during IV belimumab treatment (a score ≥0.8 was classified as adherent). Discontinuation was defined as a gap of ≥45 days in covered days during belimumab treatment.
All-cause health care costs included medical (inpatient admissions, ED visits, physician office visits, and outpatient/other ancillary visits) and pharmacy costs, and were assessed in the pre-index and post-index periods and included all costs (ie, actual reimbursements paid by health plans plus any patient cost-sharing in the form of deductibles, copayments, and coinsurance for each medical or prescription encounter incurred in the hospital setting of care). All cost estimates were adjusted for inflation to 2017 US dollars by the medical care component of the Consumer Price Index. Costs of belimumab treatment included outpatient visits for IV belimumab and belimumab prescriptions and were assessed in the post-index period only.
Statistical AnalysesAll measures were analyzed descriptively by using mean values, medians, SDs, minimum and maximum values, and interquartile ranges for continuous measures and frequency distributions for categorical variable. Pre-index and post-index period outcome comparisons were performed by using paired t tests (parametric) or Wilcoxon signed rank tests (non-parametric) for comparisons of means, and McNemar's tests for comparisons of proportions. All statistical tests performed tested a two-sided hypothesis of no difference between the pre-index and post-index periods at a significance level of 0.05.
Post hoc analyses of total hospital-based costs and total number of hospital-based service visits were conducted to further explore drivers of mean post-index costs. These costs and services included both hospital admissions and hospital ED visits, and were assessed in the ITT population during the pre-index and post-index periods. In addition, sensitivity analyses of total hospital-based costs and number of hospital-based service visits were performed in the mITT population.
DiscussionThis retrospective study assessed disease severity, HCRU, and associated costs 12 months before and 12 months after initiation of IV belimumab treatment in patients with SLE. Belimumab use was associated with reduced disease activity, as measured by the incidence and duration of flares from the pre-index to the post-index period, and with reduced OCS use, which was consistent with observed benefits from randomized controlled trials.16Furie R. Petri M. Zamani O. et al.A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus., 17Navarra S.V. Guzman R.M. Gallacher A.E. et al.Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial., 18Stohl W. Schwarting A. Okada M. et al.Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study., 19Zhang F. Bae S.C. Bass D. et al.A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea. Despite reduced disease activity in the 12-month post-index period, HCRU and associated costs were significantly increased when comparing the pre-index and post-index periods. Mean total hospital-based costs were similar but numerically greater in the post-index period, influenced by patients with outlier costs in this period. As such, post hoc analyses (75th, 90th, and 95th percentiles, removing the one patient with an outlier cost of approximately $2.5 million and truncated costs at the 90th and 95th percentiles) suggested that mean total hospital-based costs were reduced from the pre-index to the post-index period.Overall, real-world observational studies of patients with SLE treated with IV belimumab for between 6 and 24 months suggest that patient outcomes, including overall disease activity, clinical and serologic manifestations of SLE (eg, low complement, fatigue), and abnormal laboratory values typically associated with SLE (eg, white blood cell count), are improved and HCRU is reduced.25Schwarting A. Schroeder J.O. Alexander T. et al.First real-world insights into belimumab use and outcomes in routine clinical care of systemic lupus erythematosus in Germany: results from the OBSErve Germany study., 26Collins C.E. Dall'Era M. Kan H. et al.Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA., 27Babini A. Garcia M.A. Barreira J.C. Pons-Estel B. Iglesias M. Streger G. Evaluation of use of belimumab in clinical practice settings: results in Argentina., 28Cortés J. Andreu J.L. Calvo J. García-Aparicio A.M. Coronell C.G. Díaz-Cerezo S. Evaluation of Use of Belimumab In Clinical Practice Settings (Observe Study) in Spain: health resource utilization and labour absenteeism., 29Touma Z. Sayani A. Pineau C.A. et al.Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study., 30von Kempis J. Duetsch S. Reuschling N. et al.Clinical outcomes in patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: a retrospective analysis of results from the OBSErve study in Switzerland. However, in line with data shown here, an overall increase in total health care costs has been shown after initiation of IV belimumab treatment.31Ke X. Eisenberg L.D.F. Oglesby A. Patel J. Kan H. Boggs R. A retrospective administrative claims database evaluation of the utilization of belimumab in US managed care settings. Reasons for the increase in costs after IV belimumab initiation include drug acquisition cost, and they may reflect the recommended administration schedule for IV belimumab, which is dosed at 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.13FDANotably, despite the increase in hospital-based costs from the pre-index to the post-index period, the number of hospital ED visits was similar between periods. Furthermore, the proportions of patients using OCS at prednisone-equivalent doses ≥60 mg/d or ≥7.5 and <60 mg/d were reduced after IV belimumab initiation, as were the number and duration of moderate and severe flare episodes. The reasons for a lack of translation of these findings into reduced costs overall are complex, but it is possible that the patients incurring the highest hospital-based costs may have had severe comorbidities requiring multiple, costly interventions. As such, further studies are needed to understand the role of natural disease progression, including the burden of other comorbidities, and to identify real-world data sources that better characterize the potential benefits of SLE interventions via tools not routinely captured in administrative claims data; for example, via physician-reported outcomes (eg, SELENA-SLEDAI [Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index] or BILAG [British Isles Lupus Erythematosus Activity Group] for disease activity, SLE Flare Index for flares, or SLICC/ACR [Systemic Lupus International Collaborating Clinics American College of Rheumatology Damage Index] for damage accrual) and patient-reported outcomes (eg, FACIT [Functional Assessment of Chronic Illness Therapy]–Fatigue, patient global assessment, and health-related quality of life). Furthermore, the long-term benefits of SLE treatments, including belimumab, are much more difficult to capture in administrative claims data due to the time horizon required and the lack of specific ICD-9/10 diagnosis codes to identify long-term sequelae (eg, organ damage). The implication of this for the present study is that 12 months may not be a sufficient follow-up period to assess the true benefit of SLE treatment.
The statistically significant reduction in disease activity and OCS use between the 12-month pre-index to 12-month post-index period suggests that belimumab treatment may improve the quality of life of patients and their ability to work, despite the increases in observed costs. In addition, with the more recent subcutaneous belimumab indication for SLE, which does not require visits to infusion centers, the cost of belimumab therapy may decrease. However, it is also important to note that there is more to SLE than flares and health care resource utilization, including disease activity, patient-reported outcomes (eg, fatigue, health-related quality of life), and productivity. Previously, belimumab treatment has been found to significantly reduce the incidence of SLE flares.33Gatto M. Saccon F. Zen M. et al.Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Standard therapy plus belimumab treatment was found to prevent 1111 severe flares and 3631 non-severe flares over 3 years, making it cost-effective with an incremental cost-effectiveness ratio of €32,859 per quality-adjusted life-year gained.34Specchia M.L. de Waure C.
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